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The Journals of Gerontology. Series A,... Jan 2023Elevated oxidative stress (OxS), mitochondrial dysfunction, and hallmarks of aging are identified as key contributors to aging, but improving/reversing these defects in... (Randomized Controlled Trial)
Randomized Controlled Trial
Supplementing Glycine and N-Acetylcysteine (GlyNAC) in Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, and Aging Hallmarks: A Randomized Clinical Trial.
BACKGROUND
Elevated oxidative stress (OxS), mitochondrial dysfunction, and hallmarks of aging are identified as key contributors to aging, but improving/reversing these defects in older adults (OA) is challenging. In prior studies, we identified that deficiency of the intracellular antioxidant glutathione (GSH) could play a role and reported that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improved GSH deficiency, OxS, mitochondrial fatty-acid oxidation (MFO), and insulin resistance (IR). To test whether GlyNAC supplementation in OA could improve GSH deficiency, OxS, mitochondrial dysfunction, IR, physical function, and aging hallmarks, we conducted a placebo-controlled randomized clinical trial.
METHODS
Twenty-four OA and 12 young adults (YA) were studied. OA was randomized to receive either GlyNAC (N = 12) or isonitrogenous alanine placebo (N = 12) for 16-weeks; YA (N = 12) received GlyNAC for 2-weeks. Participants were studied before, after 2-weeks, and after 16-weeks of supplementation to assess GSH concentrations, OxS, MFO, molecular regulators of energy metabolism, inflammation, endothelial function, IR, aging hallmarks, gait speed, muscle strength, 6-minute walk test, body composition, and blood pressure.
RESULTS
Compared to YA, OA had GSH deficiency, OxS, mitochondrial dysfunction (with defective molecular regulation), inflammation, endothelial dysfunction, IR, multiple aging hallmarks, impaired physical function, increased waist circumference, and systolic blood pressure. GlyNAC (and not placebo) supplementation in OA improved/corrected these defects.
CONCLUSION
GlyNAC supplementation in OA for 16-weeks was safe and well-tolerated. By combining the benefits of glycine, NAC and GSH, GlyNAC is an effective nutritional supplement that improves and reverses multiple age-associated abnormalities to promote health in aging humans. Clinical Trials Registration Number: NCT01870193.
Topics: Humans; Mice; Animals; Aged; Acetylcysteine; Glycine; Health Promotion; Oxidative Stress; Aging; Glutathione; Dietary Supplements; Insulin Resistance; Inflammation; Mitochondria
PubMed: 35975308
DOI: 10.1093/gerona/glac135 -
Neuroscience and Biobehavioral Reviews Aug 2015N-acetylcysteine (NAC) is recognized for its role in acetaminophen overdose and as a mucolytic. Over the past decade, there has been growing evidence for the use of NAC... (Review)
Review
N-acetylcysteine (NAC) is recognized for its role in acetaminophen overdose and as a mucolytic. Over the past decade, there has been growing evidence for the use of NAC in treating psychiatric and neurological disorders, considering its role in attenuating pathophysiological processes associated with these disorders, including oxidative stress, apoptosis, mitochondrial dysfunction, neuroinflammation and glutamate and dopamine dysregulation. In this systematic review we find favorable evidence for the use of NAC in several psychiatric and neurological disorders, particularly autism, Alzheimer's disease, cocaine and cannabis addiction, bipolar disorder, depression, trichotillomania, nail biting, skin picking, obsessive-compulsive disorder, schizophrenia, drug-induced neuropathy and progressive myoclonic epilepsy. Disorders such as anxiety, attention deficit hyperactivity disorder and mild traumatic brain injury have preliminary evidence and require larger confirmatory studies while current evidence does not support the use of NAC in gambling, methamphetamine and nicotine addictions and amyotrophic lateral sclerosis. Overall, NAC treatment appears to be safe and tolerable. Further well designed, larger controlled trials are needed for specific psychiatric and neurological disorders where the evidence is favorable.
Topics: Acetylcysteine; Adolescent; Adult; Clinical Trials as Topic; Female; Humans; Male; Mental Disorders; Nervous System Diseases; Neurology; Psychiatry; Randomized Controlled Trials as Topic; Treatment Outcome; Young Adult
PubMed: 25957927
DOI: 10.1016/j.neubiorev.2015.04.015 -
Current Neuropharmacology 2021Oxidative stress, which results in the damage of diverse biological molecules, is a ubiquitous cellular process implicated in the etiology of many illnesses. The... (Review)
Review
Oxidative stress, which results in the damage of diverse biological molecules, is a ubiquitous cellular process implicated in the etiology of many illnesses. The sulfhydryl-containing tripeptide glutathione (GSH), which is synthesized and maintained at high concentrations in all cells, is one of the mechanisms by which cells protect themselves from oxidative stress. N-acetylcysteine (NAC), a synthetic derivative of the endogenous amino acid L-cysteine and a precursor of GSH, has been used for several decades as a mucolytic and as an antidote to acetaminophen (paracetamol) poisoning. As a mucolytic, NAC breaks the disulfide bonds of heavily cross-linked mucins, thereby reducing mucus viscosity. In vitro, NAC has antifibrotic effects on lung fibroblasts. As an antidote to acetaminophen poisoning, NAC restores the hepatic GSH pool depleted in the drug detoxification process. More recently, improved knowledge of the mechanisms by which NAC acts has expanded its clinical applications. In particular, the discovery that NAC can modulate the homeostasis of glutamate has prompted studies of NAC in neuropsychiatric diseases characterized by impaired glutamate homeostasis. This narrative review provides an overview of the most relevant and recent evidence on the clinical application of NAC, with a focus on respiratory diseases, acetaminophen poisoning, disorders of the central nervous system (chronic neuropathic pain, depression, schizophrenia, bipolar disorder, and addiction), cardiovascular disease, contrast-induced nephropathy, and ophthalmology (retinitis pigmentosa).
Topics: Acetylcysteine; Antioxidants; Expectorants; Glutathione; Oxidative Stress
PubMed: 33380301
DOI: 10.2174/1570159X19666201230144109 -
Molecules (Basel, Switzerland) Dec 2018-acetylcysteine (NAC), which is an acetylated cysteine compound, has aroused scientific interest for decades due to its important medical applications. It also... (Review)
Review
-acetylcysteine (NAC), which is an acetylated cysteine compound, has aroused scientific interest for decades due to its important medical applications. It also represents a nutritional supplement in the human diet. NAC is a glutathione precursor and shows antioxidant and anti-inflammatory activities. In addition to the uses quoted in the literature, NAC may be considered helpful in therapies to counteract neurodegenerative and mental health diseases. Furthermore, this compound has been evaluated for its neuroprotective potential in the prevention of cognitive aging dementia. NAC is inexpensive, commercially available and no relevant side effects were observed after its administration. The purpose of this paper is to give an overview on the effects and applications of NAC in Parkinson's and Alzheimer's disorders and in neuropathic pain and stroke.
Topics: Acetylcysteine; Animals; Anti-Inflammatory Agents; Antioxidants; Clinical Trials as Topic; Humans; Neurodegenerative Diseases; Synaptic Transmission
PubMed: 30551603
DOI: 10.3390/molecules23123305 -
British Journal of Pharmacology Jul 2021N-acetylcysteine (NAC) is a well-known and safe mucolytic agent, also used in patients with paracetamol overdose. In addition to these effects, recent preclinical and... (Review)
Review
N-acetylcysteine (NAC) is a well-known and safe mucolytic agent, also used in patients with paracetamol overdose. In addition to these effects, recent preclinical and clinical studies have shown that NAC exerts beneficial effects on different psychiatric disorders. Many potential mechanisms have been proposed to underlie the therapeutic effects of NAC, including the regulation of several neurotransmitters, oxidative homeostasis, and inflammatory mediators. In this paper, we summarize the current knowledge on the ability of NAC to ameliorate symptoms and neuropathologies related to different psychiatric disorders, including attention deficit hyperactivity disorder, anxiety, bipolar disorder, depression, obsessive-compulsive disorder, obsessive-compulsive-related disorder, posttraumatic stress disorder, and schizophrenia. Although preclinical studies have shown a positive effect of NAC on animal models of psychiatric disorders, the clinical efficacy of NAC is not fully established. NAC remains a strong candidate for adjunct treatment for many psychiatric disorders, but additional preclinical and clinical studies are needed.
Topics: Acetylcysteine; Animals; Anxiety; Anxiety Disorders; Bipolar Disorder; Humans; Obsessive-Compulsive Disorder
PubMed: 33760228
DOI: 10.1111/bph.15456 -
Journal of Infection and Public Health Dec 2022Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes coronavirus disease 2019 (COVID-19) and can be associated with serious complications,... (Review)
Review
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes coronavirus disease 2019 (COVID-19) and can be associated with serious complications, including acute respiratory distress syndrome. This condition is accompanied by a massive release of cytokines, also denominated cytokine storm, development of systemic oxidative stress and a prothrombotic state. In this context, it has been proposed a role for acetylcysteine (NAC) in the management of patients with COVID-19. NAC is a molecule classically known for its mucolytic effect, but it also has direct and indirect antioxidant activity as a precursor of reduced glutathione. Other effects of NAC have also been described, such as modulating the immune and inflammatory response, counteracting the thrombotic state, and having an antiviral effect. The pharmacological activities of NAC and its effects on the mechanisms of disease progression make it a potential therapeutic agent for COVID-19. NAC is safe, tolerable, affordable, and easily available. Moreover, the antioxidant effects of the molecule may even prevent infection and play an important role as a complement to vaccination. Although the clinical efficacy and dosing regimens of NAC have been evaluated in the clinical setting with small series of patients, the results are promising. In this article, we review the pathogenesis of SARS-CoV-2 infection and the current knowledge of the mechanisms of action of NAC across disease stages. We also propose NAC posology strategies to manage COVID-19 patients in different clinical scenarios.
Topics: Humans; Acetylcysteine; SARS-CoV-2; Respiratory Distress Syndrome; Immunotherapy; COVID-19 Drug Treatment
PubMed: 36410267
DOI: 10.1016/j.jiph.2022.11.009 -
Pharmacology & Therapeutics Dec 2021Initially adopted as a mucolytic about 60 years ago, the cysteine prodrug N-acetylcysteine (NAC) is the standard of care to treat paracetamol intoxication, and is... (Review)
Review
Initially adopted as a mucolytic about 60 years ago, the cysteine prodrug N-acetylcysteine (NAC) is the standard of care to treat paracetamol intoxication, and is included on the World Health Organization's list of essential medicines. Additionally, NAC increasingly became the epitome of an "antioxidant". Arguably, it is the most widely used "antioxidant" in experimental cell and animal biology, as well as clinical studies. Most investigators use and test NAC with the idea that it prevents or attenuates oxidative stress. Conventionally, it is assumed that NAC acts as (i) a reductant of disulfide bonds, (ii) a scavenger of reactive oxygen species and/or (iii) a precursor for glutathione biosynthesis. While these mechanisms may apply under specific circumstances, they cannot be generalized to explain the effects of NAC in a majority of settings and situations. In most cases the mechanism of action has remained unclear and untested. In this review, we discuss the validity of conventional assumptions and the scope of a newly discovered mechanism of action, namely the conversion of NAC into hydrogen sulfide and sulfane sulfur species. The antioxidative and cytoprotective activities of per- and polysulfides may explain many of the effects that have previously been ascribed to NAC or NAC-derived glutathione.
Topics: Acetylcysteine; Animals; Antioxidants; Humans; Hydrogen Sulfide; Sulfur
PubMed: 34171332
DOI: 10.1016/j.pharmthera.2021.107916 -
Saudi Journal of Gastroenterology :... 2022The use of N-acetylcysteine (NAC) for non-acetaminophen-induced acute liver failure (NAI-ALF) has been increasing despite controversy in its efficacy. National... (Review)
Review
The use of N-acetylcysteine (NAC) for non-acetaminophen-induced acute liver failure (NAI-ALF) has been increasing despite controversy in its efficacy. National guidelines are in disagreement for NAC use as standard of care; however, many healthcare centers continue to adopt the use of NAC outside of acetaminophen poisoning. While NAC may have multiple mechanisms of action in treatment of ALF, this has not translated to clinical benefit. Murine models have reported antioxidant and anti-inflammatory properties, as well as improvement in liver-specific microcirculation. Multiple case studies and series have reported positive outcomes of NAC treatment for ALF of various etiologies. While prospective studies suggested the benefit of NAC treatment, these studies have methodological and statistical shortcomings that affect the validity of the results. In this review, we aimed to summarize the existing literature on the efficacy of NAC for NAI-ALF including mechanism of action, case studies and series demonstrating outcomes, and prospective studies that have led to its current widespread use, along with the reported rate of adverse events.
Topics: Acetaminophen; Acetylcysteine; Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Humans; Liver Failure, Acute; Mice; Prospective Studies
PubMed: 35142656
DOI: 10.4103/sjg.sjg_406_21 -
Brain and Behavior Mar 2014There is an expanding field of research investigating the benefits of medicines with multiple mechanisms of action across neurological disorders. N-acetylcysteine (NAC),... (Review)
Review
BACKGROUND
There is an expanding field of research investigating the benefits of medicines with multiple mechanisms of action across neurological disorders. N-acetylcysteine (NAC), widely known as an antidote to acetaminophen overdose, is now emerging as treatment of vascular and nonvascular neurological disorders. NAC as a precursor to the antioxidant glutathione modulates glutamatergic, neurotrophic, and inflammatory pathways.
AIM AND DISCUSSION
Most NAC studies up to date have been carried out in animal models of various neurological disorders with only a few studies completed in humans. In psychiatry, NAC has been tested in over 20 clinical trials as an adjunctive treatment; however, this topic is beyond the scope of this review. Herein, we discuss NAC molecular, intracellular, and systemic effects, focusing on its potential applications in neurodegenerative diseases including spinocerebellar ataxia, Parkinson's disease, tardive dyskinesia, myoclonus epilepsy of the Unverricht-Lundbor type as well as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease.
CONCLUSION
Finally, we review the potential applications of NAC to facilitate recovery after traumatic brain injury, cerebral ischemia, and in treatment of cerebrovascular vasospasm after subarachnoid hemorrhage.
Topics: Acetylcysteine; Animals; Free Radical Scavengers; Humans; Nervous System Diseases
PubMed: 24683506
DOI: 10.1002/brb3.208 -
Drug Safety Mar 2021N-Acetylcysteine (NAC) is widely used in respiratory medicine, with a maximum licensed dose in chronic use of 600 mg/day; however, some clinical trials have studied the... (Review)
Review
N-Acetylcysteine (NAC) is widely used in respiratory medicine, with a maximum licensed dose in chronic use of 600 mg/day; however, some clinical trials have studied the efficacy of NAC at higher doses. The aim of this review was to evaluate the adverse effects profile of NAC at higher than the standard dose in chronic respiratory diseases to establish a risk-benefit ratio in increasing the daily dose; therefore, studies using NAC at a dose of at least 600 mg/day were selected. Forty-one articles where NAC has been used at 600 mg and above, up to 3000 mg/day, and with a specific report on safety, were considered. Most of the studies used oral NAC and were conducted on patients with chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, bronchiectasis, chronic bronchitis and cystic fibrosis. In general, the safety profile was similar at both the high and standard doses with the oral formulation; gastrointestinal symptoms were reported but they were no more common than in the control group.
Topics: Acetylcysteine; Humans; Pulmonary Disease, Chronic Obstructive
PubMed: 33326056
DOI: 10.1007/s40264-020-01026-y